Acupuncture has been used for controlling acute and chronic pain for more than 2000 years in China and is now being used in more that 60 countries including the States. The major drawbacks for acupuncture analgesia (AA) are the unpredictability of the therapeutic effects in a given individual (responder vs non-responder), and the fading of the therapeutic effects during repeated or prolonged administration of acupuncture (development of tolerance to AA). To overcome the drawbacks one should understand, first of all, why is acupuncture effective in some individuals (responders) but not in others (non-responders). We have shown that responder rats were capable of releasing large amount of opioid peptides in the central nervous system during acupuncture stimulation while non-responders were not. It remains to be studied whether the non-responders had a deficit in the gene expression and biosynthesis of the opioid peptides, or a deficit in the mechanism of opioid release from the nerve terminal storage pool. Measurement of the tissue content of the mRNA encoding prepro-enkephalin and prepro-dynorphin in the CNS of the rat in response to acupuncture stimulation, and compare the data with the peptide level and the effect of AA would help to solve this problem. The second question is to investigate the putative existence of central neuromodulators which antagonize opioid analgesia. Among the long list of putative anti-opioid peptides, the cholecystokinin octapeptide (CCK-8) is the most potent one known so far. Studies will be performed to investigate the dynamic changes of the gene expression and release of CCK-8 in the CNS of the rat and to correlate these changes with the mechanisms for non- responsiveness to AA as well as for the development of tolerance to AA. In summary, we plan to attack the goal from two opposite sides, the opioid and the anti-opioid, in an attempt to understand more deeply the mechanisms, thereby to increase the efficacy, of acupuncture analgesia.